Blood flow within the brain is characterized by dynamic spatial and temporal control. The constantly shifting patterns of regional neuronal activity and the high energy demands of active neurons necessitate local mechanisms capable of regulating blood flow in a rapid and precise manner. Parenchymal microvessels are the final cerebrovascular elements responsible for supplying these needs; however, the local mechanisms through which these vessels are regulated are poorly understood. The overall goal of this application is to improve our understanding of how local mechanisms within the brain parenchyma regulate microvascular function under physiological and pathophysiological circumstances. During the initial period of support for this work, we have: 1) developed and tested novel approaches for examining parenchymal microvessels within their normal cellular microenvironment, 2) identified key local mechanisms involved in the regulation of cerebral microvascular tone, and 3) begun to examine how microvascular function is disturbed during metabolic challenge such as occurs after stroke. The Specific Aims of this proposal are to: 1) characterize the roles of local neurons and glia in the regulation of parenchymal microvessels, and 2) elucidate pathophysiological mechanisms contributing to microvascular dysfunction. The proposed studies will provide insights into a fundamental form of intercellular signalling that is involved in coupling local blood flow to local neuronal activity in the brain. A clear understanding of the physiology nd pathophysiology of microvascular control will help identify novel strategies for limiting secondary ischemic injury to the brain.